Wilhelm Keller MD (1818-1877) and the emergence of xenobiochemistry.

Although there had been many previous inklings, the field of xenobiotic metabolism (as we know it today) began with an experiment reported in the 1841 literature proclaiming that the ingestion of benzoic acid led to the subsequent excretion of hippuric acid in human urine. A metabolic transformation undertaken by a living organism. One worker involved in the early stages of this discovery was Wilhelm Keller, although very little information about him is readily available.

Nicotinamide -Methyltransferase: Genomic Connection to Disease.

Single-nucleotide polymorphisms (SNPs) in and around the nicotinamide -methyltransferase (NNMT) gene are associated with a range of cancers and other diseases and conditions. The data on these associations have been assembled, and their strength discussed. There is no evidence that the presence of either the major or minor base in any SNP affects the expression of nicotinamide -methyltransferase.

Cytochrome P450: genotype to phenotype.

The cytochromes P450 comprise a family of enzymes that are responsible for around three-quarters of all drug metabolism reactions that occur in human populations. Many isoforms of cytochrome P450 exist but most reactions are undertaken by CYP2C9, CYP2C19, CYP2D6 and CYP3A4. This brief review focusses on the first three isozymes which exhibit polymorphism of phenotype.

Nicotinamide -Methyltransferase in Health and Cancer.

Over the past decade, the roles of nicotinamide -methyltransferase and its product 1-methyl nicotinamide have emerged from playing merely minor roles in phase 2 xenobiotic metabolism as actors in some of the most important scenes of human life. In this review, the structures of the gene, messenger RNA, and protein are discussed, together with the role of the enzyme in many of the common cancers that afflict people today.

Fate of thianthrene in biological systems.

1. Thianthrene is a sulfur-containing tricyclic molecule distributed widely within the macrostructure of hydrocarbon fossil fuels. Identified nearly 150 years ago, its chemistry has been widely explored leading to insights into reaction mechanisms and radical ion formation.

Sulphate absorption across biological membranes.

1. Sulphonation is unusual amongst the common Phase II (condensation; synthetic) reactions experienced by xenobiotics, in that the availability of the conjugating agent, sulphate, may become a rate-limiting factor. This sulphate is derived within the body via the oxygenation of sulphur moieties liberated from numerous ingested compounds including the sulphur-containing amino acids.

Molecular basis of carcinogenicity of tungsten alloy particles.

The tungsten alloy of 91% tungsten, 6% nickel and 3% cobalt (WNC 91-6-3) induces rhabdomyosarcoma when implanted into a rat thigh muscle. To investigate whether this effect is species-specific human HSkMc primary muscle cells were exposed to WNC 91-6-3 particles and responses were compared with those from a rat skeletal muscle cell line (L6-C11). Toxicity was assessed by the adenylate kinase assay and microscopy, DNA damage by the Comet assay.

Ethyl sulphate, a chemically reactive human metabolite of ethanol?

1. Ethanol consumption is known to be linked in varying degrees to numerous ailments including damage to the nervous, endocrine and musculoskeletal systems and the gastrointestinal tract as well as extensive liver injury and several cancerous events. 2.

Curiosities in drug metabolism.

1. It is inevitable that during some xenobiotic biotransformation studies, a certain metabolite or degradation product arises of which the identity is uncertain, the route of formation is ambiguous, or it is just a plain mystery. 2.

Asparagusic acid.

Asparagusic acid (1,2-dithiolane-4-carboxylic acid) is a simple sulphur-containing 5-membered heterocyclic compound that appears unique to asparagus, though other dithiolane derivatives have been identified in non-food species. This molecule, apparently innocuous toxicologically to man, is the most probable culprit responsible for the curious excretion of odorous urine following asparagus ingestion. The presence of the two adjacent sulphur atoms leads to an enhanced chemical reactivity, endowing it with biological properties including the ability to substitute potentially for α-lipoic acid in α-keto-acid oxidation systems.

Analysis of volatile organic compounds of bacterial origin in chronic gastrointestinal diseases.

Background: The aim of this study was to determine whether volatile organic compounds (VOCs) present in the headspace of feces could be used to diagnose or distinguish between chronic diseases of the gastrointestinal tract and apparently healthy volunteers.

Methods: A total of 87 people were recruited, divided between 4 categories: healthy volunteers (n = 19), Crohn's disease (n = 22), ulcerative colitis (n = 20), and irritable bowel syndrome (n = 26). They each supplied fecal samples before, and except for the healthy volunteers, after treatment.

Drug peptide conjugates in human urine?

1. Once in a while, during drug metabolism studies, an unusual or unexpected pathway is unearthed. 2.

Diversity and distribution of sulphate-reducing bacteria in human faeces from healthy subjects and patients with inflammatory bowel disease.

The relative abundance of different groups of sulphate-reducing bacteria (SRB) in faecal DNA collected before and after therapy from patients suffering from Crohn's disease (CD), irritable bowel syndrome (IBS) or ulcerative colitis (UC) has been compared with that from healthy controls. Growth tests revealed that SRB were not more abundant in samples from patients with CD before treatment than in the healthy control group. For most of the 128 samples available, these preliminary results were confirmed using degenerate PCR primers that amplify the dsrAB gene.

Is the abundance of Faecalibacterium prausnitzii relevant to Crohn's disease?

Reports that bacteria within the Firmicutes phylum, especially the species Faecalibacterium prausnitzii, are less abundant in Crohn's disease (CD) patients and supernatants from cultures of this bacterium are anti-inflammatory prompted the investigation of the possible correlations between the abundance of F. prausnitzii and the response to treatment in patients with gut diseases and healthy controls. In a randomized, double-blind trial, faeces were collected from healthy volunteers, and from patients with active CD, ulcerative colitis (UC) and irritable bowel syndrome before and after treatment.

Mitochondrial complex activity in donor renal grafts, cold ischemia time, and recovery of graft function.

Indexed mitochondrial complex activities (MCAi) were determined in biopsies obtained from 52 donor kidneys at the end of cold ischemia (8-32 hr) to see if longer anoxia affected MCAi and accounted for the increased risk of delayed graft function (DGF) in recipients of grafts with longer cold ischemia time (CIT) or from non-heart-beating donors (NHBD). CITs were significantly different between those with and without DGF (P=0.02), being shorter in the latter, but MCAi were similar.

Metabolic fate of phenothiazine in the marmoset (Callithrix jacchus).

The fate of [35S]-phenothiazine, a veterinary anthelmintic, has been investigated in the adult male marmoset (Callithrix jacchus) following oral administration. A near complete recovery of radioactivity (c. 95%) was achieved in 0-3 days, with just over one-third of the dose (c.

Inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by flavonoids: a quantitative structure-activity relationship study.

Flavonoids are commonly found in fruit and vegetables and have been shown to reach concentrations of several micromolars in human blood plasma. Flavonoids are also believed to have cancer chemoprotective properties. One hypothesis is that flavonoids are able to initiate apoptosis, especially in cancer cells, via a Ca(2+)-dependent mitochondrial pathway.

Endocrine disrupting alkylphenols: structural requirements for their adverse effects on Ca2+ pumps, Ca2+ homeostasis & Sertoli TM4 cell viability.

Alkylphenols such as nonylphenol are pollutants that are widely dispersed within our environment. They bio-accumulate within man, with levels in the muM concentration range reported in human tissues. These chemicals act as endocrine disruptors, having xenoestrogenic activity.

Effects of endocrine disruptors on dehydroepiandrosterone sulfotransferase and enzymes involved in PAPS synthesis: genomic and nongenomic pathways.

Background: Sulfation plays an important role both in detoxification and in the control of steroid activity. Studies in rodents have shown that the conversion of dehydroepiandrosterone (DHEA) to DHEA-sulfate is involved in learning and the memory process.

Methods: The effects of a range of plasticizers and related compounds commonly encountered in the environment were evaluated kinetically against human DHEA sulfotransferase (SULT 2A1) and by reverse transcriptase-polymerase chain reaction (RT-PCR) against several enzymes involved in the synthesis of the sulfotransferase cofactor adenosine 3'-phosphate 5'-phosphosulfate (PAPS).

Spot urinary creatinine excretion in pervasive developmental disorders.

Background: Excretion of creatinine in urine represents the end-point of endogenous energy transfer from stored adenosine triphosphate in skeletal and cardiac muscle. Measurement of urinary creatinine is commonly used to correct for total urine concentration. Various quantitative measures of compounds suspected to be either pathological to, or indicative of, possible therapeutic interventions for Pervasive Developmental Disorders (PDD) have relied extensively on spot creatinine as a ratio quantity, although this important metabolite has not been exclusively studied within this population.

Oxidation of combined ingestion of glucose and sucrose during exercise.

The first purpose of the study was to examine whether combined ingestion of glucose and sucrose at an intake rate of 1.2 g/min would lead to higher oxidation rates compared with the ingestion of an isocaloric amount of glucose or sucrose alone. The second aim of the study was to investigate whether a mixture of glucose and sucrose when ingested at a high rate (2.

An investigation into the inter-relationships of sulphur xeno-biotransformation pathways in Parkinson's and motor neurone diseases.

The role of defective 'sulphur xenobiotic' biotransformations in the aetiology of Parkinson's and motor neurone diseases has been in the literature for over a decade. Problems in the S-oxidation of aliphatic thioethers, sulphation of phenolic compounds and the S-methylation of aliphatic sulphydryl groups have all been reported. These reports have also been consistent in observing that only a 'significant minority' of patients express these problems in sulphur biotransformation pathways.